Targeting mitochondria with novel, differently vectorized linear phosphorylated nitrones:

authors

• Delehedde Caroline
• Thétiot-Laurent Sophie
• Esgulian Mathieu
• Chocry Mathieu
• Rockenbauer Antal
• Pietri Sylvia
• Culcasi Marcel

keywords

• Mitochondria-targeted nitrones
• 31P NMR
• EPR spin trapping
• Mitochondrial permeability
• H2O2-induced apoptosis

abstract

The free radicals (FR) occurrence in biological signalling or as pathologies triggers is well-documented and the design of specific scavengers to limit oxidative stress is enthralling. Because FR become inactivated upon addition to nitrones, efforts have focused on developing alpha-phenyl-N-tert-butylnitrone derivatives (PBNs) with promising pre-clinical data. To improve efficacy, a new generation of nitrones derived from 2-(diethoxyphosphoryl)-N-(benzylidene)propan-2-amine-N-oxide (PPNs) incorporating an antioxidant framework, gave rise to multipotent drugs exhibiting EPR-spin-trapping properties. As mitochondrial dysfunction is involved in many disorders, efforts have been concentrated on developing tools (pH probes) or pharmacological agents targeting-mitochondria. A series of mitochondria-targeted PPNs was synthesized based on the improved biocompatibility of P-containing nitrones and the expected benefits of introducing a cationic vector. Spin-adducts EPR-parameters toward biologically-relevant FR were established. Cytotoxicity was determined on cells and mitochondria-permeation assessed in isolated rat organs. New mitochondria-targeting nitrones appeared as lower cytotoxic alternative to the commonly used mito-PBN and were safely applied for investigating the anticancer-mechanism of new drugs impacting mitochondria.

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